Hpv Biology 21 Structure

The HPV genome is an 8 kbp circle of double-stranded, covalently closed, and his-tone bound DNA, which is maintained as an episome in infected cells during the productive virus life cycle. It encodes eight viral proteins across three frames (Fig. 1; see Color Plate 2, following p. 50) (18). The HPV genome is histone bound and surrounded by a 55-60 nm, nonenveloped icosahedral capsid (19) of T = 7 symmetry, which contains the genetically unrelated major capsid protein L1 and the minor capsid protein L2 (Fig. 2; see Color Plate 3, following p. 50) (20). Each capsid contains 360 L1 monomers assembled into 72 pentameric structures termed capsomeres (20). It is likely that within the HPV virion, a single copy of L2 is positioned in the center of each capsomere (unpublished data) bound to LI through two domains in L2 (21).

L1 and L2 are expressed late in the viral life cycle. The remaining six proteins are expressed earlier and are involved in viral transcription and replication (Table 2). The virus utilizes the host machinery for replication, with the exception of the viral helicase E1 and the E2 transcription factor. Initiation of replication is facilitated by interaction of E1 with E2. E2 exhibits sequence-specific binding with the viral origin of replication that contains multiple copies of its recognition motif. E2 also serves as a transcription

Fig. 1 (Color Plate 2, following p. 50). HPV genome organization. Schematic of the human papillomavirus 31 (HPV31) genome showing the arrangement of the major nonstructural and capsid genes along three frames. HPV31 mRNAs were investigated in CIN612 cells containing extrachromosomal HPV31. Four promoters were identified by primer extension, RNase protection, and nuclease 51 and ExoVII analyses (designated P77, P99, P742, and P3320 based on their respective nucleotide start sites). Adapted from reference 18.

Fig. 1 (Color Plate 2, following p. 50). HPV genome organization. Schematic of the human papillomavirus 31 (HPV31) genome showing the arrangement of the major nonstructural and capsid genes along three frames. HPV31 mRNAs were investigated in CIN612 cells containing extrachromosomal HPV31. Four promoters were identified by primer extension, RNase protection, and nuclease 51 and ExoVII analyses (designated P77, P99, P742, and P3320 based on their respective nucleotide start sites). Adapted from reference 18.

Warts Who Organization
Fig. 2 (Color Plate 3, following p. 50). HPV structure. Model of the T = 7 icosahedral capsid (~60 nm in diameter) of the HPV16 virion exhibiting distinct fivefold axial symmetry surrounding a nucle-ohistone core. Adapted from reference 20.

factor and through its multiple spliced forms regulates viral gene expression. Furthermore, E2 ensures equitable distribution of the viral genome among daughter cells during cell division by tethering the viral episomes to mitotic chromosomes (22). As the virus replicates using the host machinery, it must counteract signals for terminal differentiation of the squamous epithelium and force the keratinocytes into S phase. This is achieved by three viral oncoproteins E5, E6, and E7. E5 promotes activation of the epidermal growth factor and platelet-derived growth factor growth factor receptors. E6 triggers degradation of the checkpoint protein p53 and other key molecules, such as PDZ domain proteins through ubiquitination. E7 targets the retinoblastoma protein (pRB)

Table 2 Papillomavirus Proteins

Viral protein Gene product function

E1 Viral DNA replication

E2 Transcription factor

E4 Egress of virions

E5 Oncoprotein

E6 Oncoprotein

Role in HPVpathogenesis

Initiates viral replication by binding AT-rich sequences at the viral origin near the start site of early transcription (104); sustains ATP-dependent helicase activity (105) to catalyze the unwinding of DNA and, additionally, binds DNA polymerase subunits (106) to recruit replication machinery to viral origins Viral replication: binds to E1 in a heteromeric complex enhancing viral DNA replication by colocalization of E1 to the origin of replication (107) and abrogation of a mitotic checkpoint (108); tethering of the genome to mitotic chromosomes to ensure copies are included in both daughter cells (22) Binds cytokeratins causing collapse of the cytoskeleton (109); associates with mitochondria and induces the detachment of mictochondria from microtubules leading to a severe reduction in mitochondrial membrane potential and induction of apoptosis (110) Induces cellular proliferation and hyperplasia in response to epidermal growth factor stimulation (111,112) through modulation of the epidermal growth factor-R (113); induces transformation of cells through interaction with platelet-derived growth factor-R (114) Targets p53 and discs large (Dlg) (115) for degradation, causing genomic instability (55); targets paxillin (116) and AP1 component of clathrin-coated vesicles (117) resulting in loss of cell adhesion to substrate and disruption of cytoskeleton and cellular traffic; activation of telomerase in infected cells, extending the life of epithelial cells for production of viral progeny (118); disrupts epithelial cell-dendritic cell interactions preventing the initiation of a cell-mediated immune response and promoting survival of the virus (119); inhibits the production and responsiveness of infected cells to type 1 interferons (120)

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Table 2 (Continued)

Viral protein Gene product function Role in HPV pathogenesis

Table 2 (Continued)

Viral protein Gene product function Role in HPV pathogenesis

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